Expression of human apolipoprotein E reduces amyloid-β deposition in a mouse model of Alzheimer's disease

Holtzman, David M.; Bales, Kelly R.; Wu, Shan; Bhat, Priyanka; Parsadanian, Maia; Fagan, Anne M.; Chang, Louis K.; Sun, Yuling; Paul, Steven M.

doi:10.1172/jci6179

Cited by 349Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

Expression of human apolipoprotein E reduces amyloid-β deposition in a mouse model of Alzheimer's disease

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Holtzman, David M., Bales, Kelly R., Wu, Shan, Bhat, Priyanka, Parsadanian, Maia, Fagan, Anne M., Chang, Louis K., Sun, Yuling +1 more·1999·Journal of Clinical Investigation

DOI 10.1172/jci6179PMC PMC408154

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Abstract

The epsilon4 allele of apolipoprotein E (apo E) is associated with an increased risk for developing Alzheimer's disease (AD). This may be due to interactions between apo E and the amyloid-beta protein (Abeta). To assess the effects of human apo E isoforms on Abeta deposition in vivo, we bred apo E3 and apo E4 hemizygous (+/-) transgenic mice expressing apo E by astrocytes to mice homozygous (+/+) for a mutant amyloid precursor protein (APPV717F) transgene that develop age-dependent AD neuropathology. All mice were on a mouse apo E null (-/-) background. By nine months of age, APPV717F+/-, apo E-/- mice had developed Abeta deposition, and, as reported previously, the quantity of Abeta deposits was significantly less than that seen in APPV717F+/- mice expressing mouse apo E. In contrast to effects of mouse apo E, similar levels of human apo E3 and apo E4 markedly suppressed early Abeta deposition at nine months of age in APPV717F+/- transgenic mice, even when compared with mice lacking apo E. These findings suggest that human apo E isoforms decrease Abeta aggregation or increase Abeta clearance relative to an environment in which mouse apo E or no apo E is present. The results may have important implications for understanding mechanisms underlying the link between apo E and AD.

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The more compact plaques could be due to increased levels of the APOE protein itself, or a combination of APOE levels and differential effects of mouse versus human APOE.
“This could be due to increased levels of the APOE protein itself, or a combination of APOE levels and differential effects of mouse versus human APOE [47].”
From Astrocytic APOE3-Christchurch expression ameliorates brain amyloid-β pathology in 5xFAD mice (2026) · cites this paper as [47]
The Discussion proposes differential effects of mouse and human apo E on early amyloid-β deposition, supporting that part of the proposed explanation. But the Results report similar brain apo E levels in the human- and mouse-apo E groups, and the paper does not link either mechanism to more compact plaques. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Initial studies using PDAPP and Tg2576 APP transgenic mouse models demonstrated that the lack of murine apoE resulted in a significant decrease in Aβ deposition, along with an almost complete lack of true amyloid plaques and neuritic dystrophy.
“Initial studies using the PDAPP and Tg2576 APP transgenic mouse models that develop Aβ deposition demonstrated that the lack of murine apoE resulted in a significant decrease in Aβ deposition, along with an almost complete lack of true amyloid plaques and neuritic dystrophy (Bales et al., 1997; Holtzman et al., 2000; Holtzman et al., 1999).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Holtzman et al., 1999
The Introduction and Results report that APP V717F mice lacking murine apoE had significantly less Aβ deposition and lacked the thioflavine S-positive fibrillar deposits seen in mice expressing murine apoE. This paper examines that model, but the passages do not establish the claimed result for Tg2576 mice or an almost complete lack of neuritic dystrophy. No page numbers are provided in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Expression of human apoE isoform transgenes in PDAPP mice resulted in a marked delay in the deposition of Aβ and formation of neuritic plaques, compared to PDAPP mice expressing murine apoE or no apoE.
“The expression of human apoE isoform transgenes in PDAPP mice resulted in a marked delay in the deposition of Aβ and formation of neuritic plaques, compared to PDAPP mice expressing murine apoE or no apoE (Fagan et al., 2002; Holtzman et al., 2000; Holtzman et al., 1999).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Holtzman et al., 1999
The Results report markedly less Aβ deposition at 39 weeks in PDAPP mice expressing human apoE3 or apoE4 than in mice expressing murine apoE or no apoE. This supports delayed early Aβ deposition, but the paper does not show that formation of neuritic plaques was delayed; its reported measurements concern Aβ deposits. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Expression of mouse ApoE resulted in greater plaque formation than expression of human ApoE, and mouse ApoE preferentially promoted the formation of parenchymal plaques, while human ApoE promoted the formation of CAA.
“Expression of mouse ApoE resulted in greater plaque formation than expression of human ApoE, and mouse ApoE preferentially promoted the formation of parenchymal plaques, while human ApoE promoted the formation of CAA [59, 60, 94].”
From Alzheimer's disease: experimental models and reality (2017) · cites this paper as [60]

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Authors: Holtzman, D. M., Bales, K. R., Wu, S., Bhat, P., Parsadanian, M., Fagan, A. M., Chang, L. K., Sun, Y., & Paul, S. M.
Affiliations: Washington University in St. Louis (US)
Eli Lilly (United States) (US)
Corresponding author: Holtzman, David M.
ORCID: Holtzman, David M.
Wu, Shan
Bhat, Priyanka
Fagan, Anne M.
Chang, Louis K.
Sun, Yuling
Paul, Steven M.
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 1999-03-15
Volume: 103
Issue: 6
Pages: R15-R21
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci6179
PMC: PMC408154
OpenAlex: W2138955227
Cited by: 349
References: 60
Citations by year: 2026: 5 · 2025: 4 · 2024: 10 · 2023: 6 · 2022: 9 · 2021: 2 · 2020: 6 · 2019: 11 · 2018: 6 · 2017: 6 · 2016: 10 · 2015: 10 · 2014: 9 · 2013: 10 · 2012: 10
FWCI: 16.42
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Clinical Investigation (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Alzheimer's Association (AG13956)
Ruth K. Broad Biomedical Research Foundation
National Institutes of Health (AG13956)
National Institute on Aging (AG00861, R01AG013956, R37AG013956, AG13956)
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords: apolipoprotein E, APOE ε4, amyloid-beta deposition, Alzheimer's disease, amyloid-beta clearance, amyloid-beta aggregation
MeSH terms: Alzheimer Disease, Animals, Apolipoproteins E, Disease Models, Animal, Humans, Mice, Transgenic, Mutation, Recombinant Proteins, Amyloid beta-Peptides, Protein Isoforms, Mice

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Expression of human apolipoprotein E reduces amyloid-β deposition in a mouse model of Alzheimer's disease

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